Genomics of Cleft Palate

腭裂基因组学

• 批准号: 10475756
• 负责人: ELIZABETH JANE LESLIE
• 金额: $ 71.2万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475756
• 关键词: ATAC-seq; Address; Affect; Benchmarking; Biological; ChIP-seq; Cleft Lip; Cleft Palate; Cleft lip with or without cleft palate; Clinical; Code; Collection; Congenital Abnormality; Data; Data Set; Dental; Development; Developmental Process; Diagnosis; Epidemiology; Etiology; Face; Family; Family Study; Female; Financial Hardship; First Degree Relative; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic study; Genomics; Goals; Hearing; Hearing problem; Heart Abnormalities; Heritability; Heterogeneity; Human; Human Genetics; Individual; Inherited; Knowledge; Lead; Light; Lip structure; Mediating; Meta-Analysis; Molecular; Mus; Nasal cavity; Neurodevelopmental Disorder; Nucleotides; Operative Surgical Procedures; Oral cavity; Palate; Parents; Pathway interactions; Phenotype; Population; Population Heterogeneity; Prevention; Prognosis; Recurrence; Research; Resources; Risk; Sampling; Sex Bias; Soft Palate; Speech; Structural Congenital Anomalies; Structure; Syndrome; Techniques; Tissues; Translating; Untranslated RNA; Variant; cohort; comorbidity; congenital anomaly; congenital heart disorder; craniofacial; de novo mutation; developmental disease; feeding; functional genomics; gene discovery; genetic architecture; genetic variant; genome sequencing; genome wide association study; genomic data; high risk; high risk population; human RNA sequencing; human data; improved; insight; male; multi-ethnic; novel; orofacial cleft; palate repair; pleiotropism; precision genetics; rare variant; recruit; repaired; risk variant; single cell sequencing; transcriptome; transcriptome sequencing; transcriptomics; whole genome

PROJECT SUMMARY/ABSTRACT Cleft palate (CP) is a common craniofacial structural birth defect caused by the incomplete closure of the palate (the structure separating the oral and nasal cavities), resulting in feeding, speech, and hearing problems. CP accounts for 33% of all orofacial clefts (OFCs) or approximately 1 in 1500 babies born worldwide. Although CP is colloquially used to refer to all types orofacial clefts (e.g. cleft lip or cleft with cleft palate), CP is embryologically and epidemiologically distinct from orofacial clefts involving the lip, suggesting a unique genetic etiology. The risk of CP recurrence in first degree relatives is over 50-fold higher than the population risk, suggesting a strong genetic component. However, there have been a dearth of genetic studies for CP. Three well-powered genome-wide association studies and meta-analysis have revealed only two associated loci, neither of which account for a large portion of the genetic heritability in any population. The lack of common variant associations suggest that the etiology of CP may be similar to other congenital anomalies, such as congenital heart disease, which often result from de novo mutations, inherited rare variants, and structural variation. We propose to elucidate the genetic architecture of CP by: (1) analyzing coding and noncoding de novo, inherited, and structural variants in whole genome sequencing of over 550 case-parent trios in a well-phenotyped, multi-ethnic cohort with CP; (2) integrating these data with transcriptomic data from mouse and human palate to identify pathways underlying specific CP subtypes; and (3) determine if CP risk variants/genes show pleiotropic effects in other birth defects and developmental disorders. This project is poised to rapidly advance our understanding of the genetic etiology of CP and translate risk to families, and may lead to improved diagnosis and treatment for individuals with CP.

项目摘要/摘要 摘要腭裂是一种常见的颅面结构先天缺陷，因闭合不全而导致。 腭部(分隔口腔和鼻腔的结构)，导致进食、说话和听力 有问题。CP占所有口面部裂(OFCs)的33%，约为1500名新生儿中的1名 全世界。虽然CP在口语中用来指所有类型的口腔裂隙(如唇裂或伴有裂隙的裂隙 在胚胎学和流行病学上，CP与涉及唇部的口面部裂隙不同，提示 独特的遗传病因学。CP的一级亲属复发的风险是 种群风险，表明有很强的遗传成分。然而，基因研究一直很匮乏。 对于CP。三项强有力的全基因组关联研究和荟萃分析显示，只有两项 相关基因座，这两个基因座都不会在任何群体中占遗传遗传力的很大部分。这个 缺乏共同的变异关联提示CP的病因可能与其他先天性疾病相似 先天性心脏病等畸形通常是由从头突变引起的，遗传性很少见 变异和结构变异。我们建议通过以下方式阐明CP的遗传结构：(1)分析 超过550个全基因组测序中的编码和非编码从头开始、遗传和结构变异 在一个表型良好的多民族CP队列中的病例-父母三人组；(2)将这些数据与 从小鼠和人的味觉中转录数据，以确定特定CP亚型的潜在途径；以及 (3)确定CP风险变异/基因在其他出生缺陷和发育中是否表现出多效性效应 精神错乱。这一项目将迅速推进我们对慢性支气管炎和慢性阻塞性肺疾病的遗传病因的理解。 将风险转移到家庭，并可能导致改善对CP患者的诊断和治疗。